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RAD51 135G→C Modifies Breast Cancer Risk among BRCA2 Mutation Carriers: Results from a Combined Analysis of 19 Studies

2007; Elsevier BV; Volume: 81; Issue: 6 Linguagem: Inglês

10.1086/522611

1537-6605

Antonis C. Antoniou, Olga M. Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L. Neuhausen, Jeffery P. Struewing, Dominique Stoppa‐Lyonnet, Laure Barjhoux, David J. Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Susan M. Domchek, Katherine L. Nathanson, Judy E. Garber, Jeffrey N. Weitzel, Steven A. Narod, Gail E. Tomlinson, Olufunmilayo I. Olopade, Andrew K. Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mrs Clare Rogers, Peter A. Daly, Huw Dorkins, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B. Spurdle, Xiaohong Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L. Andrulis, Eduard Ilyushik, Hilmi Özçelik, Peter Devilee, Maaike P.G. Vreeswijk, Mark H. Greene, Sheila A. Prindiville, Ana Osório, Javier Benítez, Michal Zikán, Csilla I. Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Aðalgeir Arason, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix‐Trench,

DNA Repair Mechanisms

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.